Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
  • C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group

Definitions

• the invention relates to novel amino derivatives of aryl 3H 1,4 benzodiazepin 2(1H) ones, intermediates therefor, and processes of making the foregoing. More specifically, the invention relates to 5-aryl-3H-1,4- benzodiazepin-2(1H)-ones containing a tertiary amino group in either the 7-position or on the S-aryl ring moiety.
• novel tertiary amino-containing 5-aryl-3H-1,4- benzodiazepin-2(1H)-ones and derivatives thereof to which the invention relates are selected from the group consisting of compounds of the formula and pharmaceutically acceptable salts thereof; wherein A is selected from the group consisting of R R and R1 are selected from the group consisting of hydrogen and lower alkyl; R and R are selected from the group consisting of hydrogen, halogen, lower alkoxy, lower alkyl and trifluoromethyl; at least one of R and R is and R and R are selected from the group consisting of, individually, lower alkyl and, taken together with the nitrogen atom, a monoheterocyclic ring containing, at the most, one further hetero atom selected from the group consisting of nitrogen and oxygen.
• R2 it is preferred that R be selected from the group consisting of hydrogen, halogen, lower alkoxy, lower alkyl and trifluoromethyl. Moreover, when R is it is preferable that R be selected from the group consisting of hydrogen, halogen, lower alkoxy, lower alkyl and trifluoromethyl.
• R and R when individual radicals, represent straight or branched chain lower alkyl groups such as methyl, ethyl, propyl, isopropyl or the like and, when taken together with the nitrogen atom to which they are attached, can form a monoheterocyclic ring containing, at the most, one further hetero atom selected from the group consisting of nitrogen and oxygen.
• monoheterocyclic rings containing 5 to 6 members such as piperidino and morpholino and the like.
• Such carbon atoms can individually comprise a part of the said straight or branched chain aliphatic radical such as methyl, ethyl, propyl, isopropyl or the like.
• such carbon atoms can comprise part of a divalent radical, and such radicals can combine with each other directly or through the said, at the most, one further hetero atom to form a group such pentamethylene and ethyleneoxyethylene.
• R R and R represent either hydrogen or straight or branched chain lower alkyl such as methyl, ethyl, propyl, isopropyl and the like.
• R and R are either hydrogen, lower alkoxy such as methoxy and the like, lower alkyl such as methyl and the like, trifiuoromethyl or halogen.
• halogen includes all four halides, and especially preferred is chlorine.
• the pharmaceutically acceptable salts of said compounds form pharmaceutically acceptable acid addition salts with pharmaceutically acceptable organic and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phos phoric acid, nitric acid, tartaric acid, citric acid, camphor sulfonic acid, ethane sulfonic acid, toluene sulfonic acid, ascorbic acid, salicylic acid, maleic acid, succinic acid, mandelic acid, formic acid, acetic acid and the like.
• pharmaceutically acceptable organic and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phos phoric acid, nitric acid, tartaric acid, citric acid, camphor sulfonic acid, ethane sulfonic acid, toluene sulfonic acid, ascorbic acid, salicylic acid, maleic acid, succinic acid, mandelic acid, formic acid, acetic acid and the like.
• compounds of Formula I above form pharmaceutically acceptable quaternary ammonium salts with conventional quaternizing agents such as lower alkyl halides, lower alkyl sulfates, aralkyl halides and aralkyl sulfates.
• the compounds of Formula I above can be prepared by a variety of methods.
• One method for preparing compounds for the formula 7- (R R N) -1R -3-R (R -phenyl) -3H-1,4- benzodiazepin-2( lH)-ones wherein R R R R and R have the same meaning as ascribed thereto hereinabove utilizes 5-halo-2-nitrobenzophenone as a starting material. These compounds are not part of this invention but are disclosed hereinbelow in order that the present disclosure may be complete. These 5-halo-2-nitrobenzophenones, upon treatment with the appropriate secondary amine, yield compounds of the formula wherein R R and R have the same meaning as above.
• This reaction can be conducted either in conventional inert organic solvents, such as ethanol, dioxane or the like.
• the amine being reacted such as dimethylamine, piperidine, morpholine, or the like, can itself serve as the reaction medium.
• the treatment is preferably carried out at an elevated temperature.
• the so-obtained 5-(N-substituted-amino)-2-nitrobenzophenone is reduced to the corresponding S-(N-substituted-amino)-2-aminobenzophenone.
• This reduction can conveniently be effected via hydrogenation in the presence of a hydrogenation catalyst, such as Raney nickel, and in the presence of a conventional inert organic solvent, such as ethanol, or the like.
• One method for preparing compounds of the formula of 7-R -5 (R R N-phenyl)-1-R -3-R -3H-1,4-benzodi-azepin-(lH)-ones wherein R R R R and R have the same meaning as ascribed thereto hereinabove involves utilization of Z-aminobenzophenones having the formula of wherein R R and R have the meanings ascribed thereto hereinabove.
• the S-(N-substituted amino)-2-aminobenzophenone and the compounds of Formula II above can thereafter be treated to form the compounds corresponding to Formula I above.
• the Z-aminobenzophenones can be isolated in the form of a mineral salt and can then be reacted with an a-amino acid to directly prepare compounds of Formula I above wherein A is In those compounrs wherein R is hydrogen, the a-amino acid utilized is glycine. Where R is lower alkyl, ocamino acids having the formula R CI-I(NH )-COOH are used to introduce the group R into the final compound. Alanine, for example, is exemplary of such ozamino acids.
• the reaction of the Z-aminobenzophenones with an u-amino acid is carried out with an a-amino acid ester such as a lower alkyl ester of an a-amino acid and is preferably effected in the presence of an inert organic solvent such as pyridine, dimethylformamide or the like. It is also preferable to utilize one of the materials or a fraction thereof present in the form of the salt of a strong organic or inorganic acid such as glycine hydrochloride, glycine ethyl ester hydrochloride, pyridine hydrochloride or the like.
• a strong organic or inorganic acid such as glycine hydrochloride, glycine ethyl ester hydrochloride, pyridine hydrochloride or the like.
• the S-(N-substituted amino)-2-aminobenzophenone described above, or the compounds corresponding to Formula II above are reacted with an u-hal'o-lower alkanoyl halide to form either a S-(N-substituted amino)-2-(a-halo lower alkanoylamino)-benzophenone or a Z-(a-halo lower alkanoylamino)-benzophenone having a tertiary amino group in the prime position which can then be reacted with ammonia to yield the final product of Formula I above wherein A is Compounds of Formula I above wherein A is ie the 4,5-dihydro derivatives, can be prepared from compounds of Formula I above wherein A is by reduction. For example, the latter compounds can be reduced with hydrogen in the presence of a hydrogenation catalyst such as platinum oxide to yield the former compounds.
• a hydrogenation catalyst such as platinum oxide
• Another method for preparing compounds of Formula I above wherein R is a tertiary amino group comprises the reductive alkylation of a compound of the formula R3 at Q CH-R4 O N 2 A In wherein A, R and R have the same meaning as above.
• This reductive alkylation is preferably conducted using hydrogen as a reducing agent in the presence of a hydrogenation catalyst such as Raney nickel.
• a hydrogenation catalyst such as Raney nickel.
• formaldehyde is used as the alkylating agent.
• This reductive alkylation can be conducted at room temperature or elevated temperatures, and is preferably conducted in the presence of conventional inert organic solvents such as methanol, ethanol or the like.
• R is lower alkyl
• compounds of Formula I above wherein R is hydrogen by forming the alkali metal salt thereof and reacting such salt with dilower alkyl sulfate, lower alkyl halide or similar alkylating agents in an inert organic solvent medium such as ether, benzene, alcohol, dimethylformamide, dioxane or the like, preferably at room temperature or below.
• inert organic solvent medium such as ether, benzene, alcohol, dimethylformamide, dioxane or the like, preferably at room temperature or below.
• Compounds of Formula I above wherein R is lower alkyl can be prepared similarly from compounds of Formula I above wherein R is hydrogen by reacting the latter with an alkylating agent of the type specified immediately hereinabove in the presence of an inert organic solvent.
• a compound of Formula I above wherein R is hydrogen can be reacted with a sodium alkylate to form a sodioderivative of the former, and this derivative can be reacted with an alkylating agent such as a lower alkyl halide to form a compound corresponding to Formula I above wherein R is lower alkyl.
• the compounds of Formula I above are useful as sedatives, muscle relaxants and anticonvulsants.
• the compounds of Formula 1, their pharmaceutically acceptable acid addition salts, and their pharmaceutically acceptable quaternary ammonium salts can be administered internlly, i.e. parenterally or enterally, by incorporating therapeutic dosages in conventional pharmaceutical liquid or solid vehicles to provide elixirs, suspensions, tablets, capsules and the like according to accepted pharmaceutical practice.
• Example 1 To a solution of 10 g. of -chloro-2-nitrobenzophenone in 150 ml. of ethanol was added a solution of approximately 22 g. of dimethylamine in 100 ml. of ethanol. The mixture was heated in an autoclave under nitrogen atmosphere to 110 for 24 hours. The alcoholic solution was concentrated in vacuo and cooled. Yellow needles of 5-dimethylamino-Z-nitrobenzophenone separated which were collected on a filter and after recrystallization from alcohol melted at 130-132.
• reaction mixture was washed successively with two 200 cc. portions of ice water, two 200 cc. portions of cold 10% sodium carbonate and finally with 200 cc. of 10% sodium chloride solution. Emulsions were broken by filtration through a thin pad of diatomaceous earth. The methylene chloride solution was dried over magnesium sulfate and evaporated in vacuo (50) leaving a thick oily residue which soon crystallized exothermically yielding 2- nitro-5-chlorobenzophenone which upon recrystallization from 30 cc. of methanol melted at 87-89.
• Example 2 A solution of 3 g. of 5-chloro-2-nitrobenzophenone in 50 ml. of piperidine was refluxed for 72 hours. Excess piperidine was removed in vacuo. The residue was dissolved in a mixture of Water and ether. The ether phase was dried and on evaporation yielded orange needles of 2-nitro-S-piperidinobenzophenone, which after recrystallization from a mixture of benzene and hexane melted at 109-111.
• Example 3 A solution of 3 g. of 5-chloro-2-nitrobenzophenone in 50 ml. of morpholine was refluxed for 18 hours. Excess morpholine was removed in vacuo yielding an oil which was poured into ice water. Crystals formed which were collected on a filter and recrystallized from methanol. Yellow leaflets of 5-morpholino-2-nitrobenzophenone melting at l52l54 were obtained.
• Example 4 A mixture of 6.2 g. of 2-nitro-5-piperidinobenzophenone, 1500 ml. of ethanol and approximately 0.5 g. of Raney nickel was shaken at 25 and normal pressure under an atmosphere of hydrogen. The uptake was 1450 ml. of hydrogen (ca 0.06 mole). After filtering from the catalyst the solution was concentrated in vacuo to a volume of 100 ml. and 15 ml. of a 4 N solution of hydrogen chloride in ethanol was added. Slow addition of ether to this solution precipitated crystals of 2-amino- 5-piperidinobenzophenone monohydrochloride, which upon recrystallization from a mixture of ethanol and ether yielded yellow needles melting at 227-240 (dec.).
• Example 5 A mixture of 5g. of 2-amino-5-piperidinobenzophenone monohydrochloride and 35 g. of glycine ethyl ester hydrochloride was refluxed for 17 hours in 100 ml. of pyridine. The pyridine was removed in vacuo and the residue stirred with water. The solid was collected on a filter and recrystallized from ethanol. Yellow prisms of 5-phenyl-7-piperidino-3H-1,4-benzodiazepin-2(1H)-one melting at 250252 where obtained.
• Example 6 To a solution of 56 g. of 7-nitro-5-phenyl-3H-l,4-benzo- -diazepin-2(1H)-one in 800 ml. of methanol was added 80 ml. of a 37% aqueous solution of formaldehyde and ca. 8 g. of Raney nickel. This mixture was shaken for 22 hours and ca. 20 atm. of hydrogen pressure. The solution was filtered from the catalyst and concentrated yielding yellow needles of 7 dimethylamino 5-phenyl-3H-1,4- benzodiazepin-2-(lH)-one, Which upon recrystallization from ethyl acetate gave crystals melting at 245247.
• reaction product 5-phenyl-3H-1,4-benzodiazepin-2(1H)- one, crystallized out, was filtered off and then recrystallized from acetone in the form of colorless rhombic prisms, M.P. 182-183.
• Example 7 To a solution of 25 g. of 1-methyl-7-nitro-5-phenyl- 3H-1,4-benzodiazepin-2(1H)-one in 600 ml. of methanol was added 50 ml. of a 37% solution of aqueous formaldehyde and ca. 8 g. of Raney nickel. This mixture was shaken under an initial pressure of 8 atm. hydrogen. After 2 to 3 hours the theoretical amount (5 moles of hydrogen per mole of substance) had been taken up and the pressure remained constant. The solution was filtered from the catalyst and the main amount of methanol was removed in vacuo.
• Example 8 A solution of 5 g. of 7-dimethylamino-5-phenyl-3H-1,4- benZodiazepin-2(1H)-one in ml. of acetic acid was hydrogenated with 0.3 g. of platinum oxide at 25 and 1 atm. After 2 hours the uptake of hydrogen had stopped and the solution was filtered from the catalyst. On neutralization with aqueous ammonia a white solid precipitated which was collected on a filter. Dissolving in hot ethanol and cooling produced crystals of 4,5-dihydro-7- dimethylamino-5-phenyl-3H-l,4 benzodiazepin 2(1H)- one which after recrystallization from the same solvent yielded white platelets melting at 174-176".
• Example 9 A solution containing 5.6 g. of 7-dimethylamino-1- methyl-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one and 10 g. of methyl bromide in 60 ml. of acetone was kept at room temperature for 24 hours. After this time brown crystals had separated which were collected on a filter. Recrystallization from methanolether gave colorless prisms of (1,2-dihydro-1-methyl-2-oxo-5-phenyl-3H-1,4 benzodiazepin-7yl)trimethylammonium bromide melting at 190 (dec.).
• Example 10 To a solution of 10 g. of 5(2-chlorophenyl)-7-nitro-3H- 1,4-benzodiazepin-2(1H)-one in 275 ml. of methanol was added 20 ml. of a 37% aqueous solution of formaldehyde and ca. 5 g. of Raney nickel. This mixture was shaken over night under an initial pressure of 5-6 atm. of hydrogen. The solution was filtered from the catalyst and evaporated in vacuo. The residue was recrystallized from ethyl acetate to yield yellow needles of 5-(2-chlorophenyl) -7-dimethylamino-3H-1,4-benzodiazepin 2 1H one melting at 245248.
• Example 11 To a solution of g. of 7-nitro-5-(a,ot,ot-trifluoro-otolyl)-3H-1,4-benzodiazepin-2(1H) one in 800 ml. of methanol was added 50 ml. of a 37% aqueous solution of formaldehyde and ca. 8 g. of Raney nickel. This mixture was shaken over night under an initial pressure of ca. 20 atm. of hydrogen. The solution was filtered from the catalyst and evaporated in vacuo.
• a solution of o-trifluoromethyl phenyl magnesium bromide was prepared in the usual manner from 50.0 g. of o-bromo-benzotriiluoride, 5.55 g. of magnesium and 110 ml. of anhydrous ether.
• the Grignard reagent can also be prepared by reacting 39.7 g. of o-chlorobenzotrifluoride with 5.55 g. or" magnesium in tetrahydrofurane. This solution was added With stirring at 20 C. over a period of 3 hours to a solution of 33.0 g. of 2-methyl-4H- 3,1-benzoxazin-4-one in 300 ml. of methylene chloride.
• Example 12 To a solution of 6 g. of 5-(2-chlorophenyl)-7-dimethylamino-3H-1,4-benzodiazepin-2(1H)-one in ml. of dimethylformamide 1.25 g. of solid sodium methoxide was added with stirring. The mixture was cooled to 0 and a solution of 4 g. of methyl iodide in 50 ml. of dimethylformamide was added dropwise. The temperature was maintained between 0 and 10. The excess of methyl iodide was removed in vacuo without heating and the solution was poured into ice water. The aqueous phase was extracted with ether, the ether was washed with water, dried and evaporated.
• Example 14 To a solution of 7.3 g. of 1-methyl-7-nitro-5-(a,a,atrifluoro-o-tolyl) 3H-l,4-benzodiazepin 2(1H)-one in 275 m1. of methanol was added 25 ml. of a 37% aqueous solution of. formaldehyde and ca. 4 g. of Raney nickel. This mixture was shaken for 4 hours and at an initial pressure of 14 atm. hydrogen. The resulting solution was filtered from the catalyst and the methanol then evaporated in vacuo. The residue was dissolved in ether and dried with sodium sulfate.
• Example 15 A solution of 8.8 g. of 7-dimethylamino-l-methyl-S- phenyl-3H-1,4-benzodiazepin-2(1H)-one in 150 ml. of acetic acid was hydrogenated with 0.3 g. of platinum oxide at 25 and 1 atm. After 1 hour the uptake of hydrogen had stopped and the solution was filtered from the catalyst. On neutralization with sodium hydroxide white flocks separated which were extracted with dichloromethane. The organic phase was washed with water and dried over sodium sulfate.
• Example 16 To a solution of 8 g. of 2',5-dichloro-2-nitrobenzophenone in 175 ml. of ethanol there was added a solution of app. 5 g. of dimethylamine in 25 ml. of ethanol. The mixture was heated in an autoclave under nitrogen atmosphere to 90 for 20 hours and the resulting solution concentrated in vacuo and cooled. Yellow prisms of 2'-chloro-5-dimethylamino-2-nitrobenzophenone separated and were collected on a filter and, after recrystalliation from methanol, melted at 156-158.
• Example 17 A solution containing 5 g. of 5-chloro-2-nitrobenzophenone and 22 g. of diethylamine in 50 ml. of ethanol was heated in an autoclave to -140 for 24 hours. The alcoholic solution was concentrated in vacuo and cooled. On addition of a small amount of water, yellow prisms of 5-diethylamino-2-nitrobenzophenone separated and after recrystallization from a mixture of ethanol and water melted at approximately 70.
• Example 18 A mixture of 15.8 g. of 2-amino-5-chloro-2-piperidinobenzophenone and 21 g. of glycine ethyl ester hydrochloride was refluxed for 18 hours in 100 ml. of pyridine containing 1 ml. of piperidine. Approximately 75 ml. of pyridine was removed by distillation and the residue was then cooled and partitioned between methylene chloride (100 ml.) and water (1 1.). The methylene chloride layer was washed with water (3 x 100 ml.). The solvents were then removed under reduced pressure.
• Example 19 A solution of 17.6 g. of 2-amino-5-chloro-2'-dimethylaminobenzophenone and 15.5 g. of bromoacetyl bromide in 200 ml. of benzene was refluxed for 90 minutes. 100
• Example 1 To a solution of 4.0 g. of 7-chloro-5-(2-dimethylaminophenyl)-3H l,4-benzodiazepin-2(1H)-one in ml. of dimethylformamide was added, with stirring, a solution of 0.825 g. of sodium methoxide in 3 ml. of methanol. The mixture was cooled to 0 and a solution of 3.62 g. of methyl iodide in 50 ml. of dimethylformamide was added dropwise. The temperature was maintained between 0 and 10. The excess of methyl iodide was removed in vacuo without heating, and the solution was poured into ice water.
• Example 21 A mixture of platinum oxide (1.0 g.) and 150 cc. of acetic acid was reduced at atmospheric pressure and at room temperature. To the suspension of the reduced catalyst, a solution of 9.5 g. of 7-chloro-5-(2-dimethylaminophenyl)-3H-1,4-benzodiazepin-2(1H)-one in 200 ml. of acetic acid was added and the mixture hydrogenated to completion. Filtration of the catalyst over Hy-flo, using suction and concentration of the filtrate under reduced pressure, gave a residue.
• Example 22 A solution of 4.0 g. of 7-chloro-4,5-dihydro-5-(2-dimethylaminophenyl)-3H-1,4-benzodiazepin-2(1H)-one in 25 m1. of N,N-dimethylformamide was treated with a solution of 0.825 g. of sodium methoxide in methanol and heated on the steam bath for 10 minutes. The mixture was cooled to room temperature. 3.86 g. of methyl iodide was added and the solution was thereafter stirred at 60 for 3.5 hours and then at room temperature for 11 hours. N,N-dimethylformamide was removed under reduced pressure and the residue partitioned between benzene cc.) and water (100 cc.).
• the dihydvrochloride salt of the above compound was prepared by dissolving the base in methanol and saturating the solution with hydrogen chloride. Evaporation of the methanol left a crystalline residue which was recrystallized from methanol to give, as white rods, 7-chloro- 4,5 dihydro-1,4-dimethyl-5-(2 dimethylaminophenyl)- 3H-1,4-benzodiazepin-2(1H)-one dihydrochloride, M.P. 152l63.
• Example 23 To a solution of 12 g. of 2',5-dichloro-2-nitrobenzophenone in 200 ml. of ethanol there was added a solution of app. 50 g. of dimethylamine in 100 ml. of ethanol. The mixture was heated in an autoclave under nitrogen atmosphere to for 36 hours and the resulting solution concentrated in vacuo and cooled. Yellow platelets 2',5-bis(dimethylamino) 2-nitrobenzophenone separated and were collected on a filter and after recrystallization from ethanol melted at 187-189".
• a compound selected from the group consisting of compounds of the formula and pharmaceutically acceptable salts thereof wherein A is selected from the group consisting of R R and R are selected from the group consisting of hydrogen and lower alkyl; R and R are selected from the group consisting of hydrogen, halogen, lower alkoxy, lower alkyl and trifluoromethyl; at least one of R and R is and R and R are selected from the group consisting of, individually, lower alkyl and, taken together with the nitrogen atom, a 6-membered monoheterocyclic ring containing, at the most, one further hetero atom selected from the group consisting of nitrogen and oxygen, said further hetero atom being para to the said nitrogen atom in the ring.
• R and R are selected from the group consisting of, individually, lower alkyl and, taken together with the nitrogen atom, a 6-mernbered monoheterocyclic ring containing, at the most, one further hetero atom selected from the group consisting of nitrogen and oxygen, said further hetero atom being para to the said nitrogen atom in the ring;
• R and R are se lected from the group consisting of hydrogen and lower alkyl and R is selected from the group consisting of hydrogen, halogen, lower alkoxy, lower alkyl, trifluoromethyl and 3.
• R and R are selected from the group consisting of hydrogen and lower alkyl;
• R is selected from the group consisting of hydrogen, halogen, lower alkoxy, lower alkyl and trifluorornethyl and
• R and R are selected from the group consisting of, individually, lower alkyl and, taken together with the nitrogen atom, a 6-membered monoheterocyclic ring containing, at the most, one further hetero atom selected from the group consisting of nitrogen and oxygen, said further hetero atom being para to the said nitrogen atom in the ring.
• R is which comprises the reductive alkylation of a compound of the formula I C H-R4 OgN- wherein A, R R R and R have the same meaning as in claim 1.

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• 1963
  • 1963-06-07 US US286169A patent/US3218315A/en not_active Expired - Lifetime
• 1964
  • 1964-06-02 GB GB22736/64A patent/GB1013458A/en not_active Expired
  • 1964-06-03 FR FR976837A patent/FR3609M/fr not_active Expired
  • 1964-06-04 BE BE648825D patent/BE648825A/xx unknown
  • 1964-06-05 NL NL6406381A patent/NL6406381A/xx unknown
  • 1964-06-06 ES ES300711A patent/ES300711A1/es not_active Expired

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